This invention relates to methods and materials involved in the treatment of non-fungal induced mucositis of the distal intestinal tract, including pouchitis.
Total abdominal colectomy with the subsequent creation of an ileal pouch (IPAA) has become the treatment of choice for unremitting ulcerative colitis and polyposis syndromes. The development of an idiopathic acute and active chronic inflammation in these surgically constructed ileal reservoirs, a clinical entity referred to as pouchitis, is the most common long-term complication of this procedure. The incidence of pouchitis is cumulative and ultimately effects 50-60% of pediatric and adult patients with ulcerative colitis in this country (or about 75,000 patients in total) who undergo colectomy. Its prevalence appears to be similar in pediatric and adult patient populations.
The pathogenesis of pouchitis remains a mystery. As such, treatments for this disorder have been largely empiric and have relied on the use of oral or topically applied antibiotics or immunosuppressive agents. However, there is a growing body of patients with pouch disease that is refractory to all presently available therapies. Persistent pouch inflammation in these patients, manifest clinically as abdominal cramping, rectal bleeding, and fecal incontinence can be medically and socially disabling.
The transmigration of polymorphonuclear white blood cells (PMNs) across intestinal epithelia contributes to the mucosal damage that occurs in infectious and inflammatory gastrointestinal diseases including pouchitis. Effective pharmacologic approaches to reduce or eliminate this cellular response could have a high impact on the clinical outcome of patients experiencing intestinal inflammation.
Certain azole compounds such as clotrimazole have been used both topically and systemically as antifungals. For example, U.S. Pat. No. 6,207,703 teaches the use of these antifungal compounds for the treatment of diseases associated with fungal infections; non-invasive fungus induced conditions such as chronic otitis media, chronic colitis and Crohn's disease. More recently, studies have identified other uses for such imidazoles. U.S. Pat. No. 5,273,992 revealed that these imidazoles regulate Ca++ activated K+ channels in erythrocytes, and are thus useful in treating sickle cell anemia, which involves the inhibition of potassium transport; and U.S. Pat. No. 6,495,567 teaches the use of azoles for the treatment of diarrhea and scours. Similarly, U.S. Pat. No. 6,545,028 discloses that certain azole compounds, including clotrimazole (CLT), because of their inhibitory activity on Ca++ activated potassium channels can be used for the treatment of diseases such as inflammatory bowel disease, Crohn's disease, dermatitis, psoriasis etc. These azoles have also been found to be effective in inhibiting endothelial and/or vascular smooth muscle cell proliferation. The results of this finding are described in U.S. Pat. No. 5,358,959 and U.S. Ser. No. 08/018,840, which discloses using clotrimazole for treating atherosclerotic and angiogenic conditions, respectively. Non-imidazole metabolites and analogs of the foregoing compounds also have been described as useful in treating the foregoing conditions (see U.S. Ser. Nos. 08/307,874 and 08/307,887). Clotrimazole also has been found to inhibit cellular proliferation and has been proposed as an anti-cancer agent. It was subsequently discovered that the anti-proliferative effects were mediated by the tri-aryl portion of the molecule, and tri-aryl derivatives were proposed for inhibiting cancer cell growth and cellular proliferation responsible for inflammatory diseases. (See U.S. Pat. No. 6,331,534).
Previous studies have demonstrated that CLT and related antifungal agents inhibit the chemotaxis of PMNs across membrane filters. Previous investigators have demonstrated that CLT and related antifungal compounds have been shown to affect PMN migration towards chemotactic gradients in-vitro without effecting PMN function or antimicrobial activity as assessed by in-vitro killing assays. These in-vitro effects prompted an evaluation of the potential clinical utility of oral CLT therapy in the treatment of rheumatoid arthritis, a disorder characterized histologically by the recruitment of activated PMN's across synovial membranes and into joint spaces. Outcome data from these studies did not reach statistical significance, and the adverse effects associated with systemic administration of CLT proved to be dose-limiting.